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Copper has long been implicated as a contributory factor in the development of Alzheimer's disease, but the role of this divalent cation remains controversial. In this week's PNAS early online edition, Larry Sparks, Sun Health Research Institute, Sun City, Arizona, and Bernard Schreurs, West Virginia University, Morgantown, report that, depending on the diet, even minor amounts of the metal can lead to both amyloid plaques and a memory deficit in rabbits.

The diet to elicit these effects, it turns out, is one supplemented with two percent cholesterol. When Sparks fed rabbits such a cholesterol diet for 10 weeks, then examined various regions of the brain, he found that the animals had almost twice as many Aβ-immunoreactive neurons in the cortex as did rabbits spared the cholesterol. In the temporal cortex, for example, cholesterol-fed rabbits had, on average, 108 such neurons per square mm, vs. 58 in rabbits fed normal chow.

Copper exacerbated this difference. When Sparks added 0.12 ppm copper sulfate to the distilled water supply, the number of immunoreactive neurons almost doubled again, to 174/sq mm. Similar effects were seen in the superior cortex (176/sq mm, 98/sq mm, and 54/sq mm, for cholesterol/copper, cholesterol, and normal diet, respectively), and the hilus, while about a 1.5-fold increase was observed in the hippocampus. All these increases were statistically significant. However, the metal had very little effect on neurons in the parietal cortex. The antibody used, 10D5, which reacts with the first 16 amino acids in the N-terminal of Aβ, also revealed some extracellular deposits, or senile plaque-like structures, in the copper-fed animals, but not in the controls.

The metal also interfered with the rabbits' ability to learn a conditioned response. Sparks tested this by exposing the animals to an audible tone that was followed half a second later with a small blast of air. After eight sessions of conditioning, control rabbits anticipated the air puff about 60 percent of the time; rabbits fed copper, however, were much less successful, reacting before the air puff only 10 percent of the time.

This is not the first time copper has been linked to cholesterol and Aβ metabolism. Low density lipoprotein, a cholesterol carrier, has been shown to exacerbate the neurotoxic effect of copper-laced AβPP (see ARF related news story), while the copper chelator clioquinol has been shown to reduce amyloid burden in the brain (see ARF related news story). What's striking about this recent study is the minute levels of copper needed to exacerbate the effects of cholesterol-about 10-fold less than the 1.3 ppm limit for drinking water (U.S.) set by the Environmental Protection Agency.

What all this means for humans is uncertain. It is known that in certain cases, such as the copper transport disease tricholipodystrophy, otherwise known as Menke's or kinky hair disease, grossly elevated copper levels do not lead to dementia. "But it is a two-stage process," explains Sparks. "Copper itself may have no effect unless there is an overproduction of Aβ induced by cholesterol."—Tom Fagan